The NHGRI Embryonic Stem Cell and Transgenic Mouse Core provides a shared service to NHGRI investigators. The Core specializes in generating genetically engineered mice (GEM) via conventional transgenesis, ES cell targeting, and more recently genome editing using site-specific nucleases (CRISPR/Cas). To do this work, the Core breeds, in-house, 90% of the animals to be used for generating GEM. The Core utilizes several background strains for generating mice and has developed and characterized embryonic stem cells from C57Bl/6J, C57Bl/6N, C57Bl/6 albino, 129S6Sv/Ev, and 129.B6(GFP). We also have a colony of various Cre expressing mice and other transgenics that are used by investigators across many protocols, thereby maximizing the efficiency and reducing mouse numbers by breeding for multiple users. All important mice are cryopreserved and stored in 2 separate locations for disaster purposes. All imported mice are rederived into the Core by in vitro fertilization. We routinely genotype mice and have adapted efficient protocols to minimize mice, reagents and time. The Core supports NHGRI investigators in construct design for gene targeting and transgenesis, and in basic manipulations of mouse husbandry. Other services provided by the Core to help serve NHGRI investigators include ENU injection, teratoma analysis, embryo harvest and dissection, isolation of mouse embryonic fibroblasts and generation of induced pluripotent stem cells. These services allow NHGRI investigators to take full advantage of the mouse as a model organism. Thus, the Core not only generates mice, but we facilitate and enable investigators to perform mouse experiments in areas where they have less expertise. The NHGRI Transgenic Core is at the forefront of a major increase in transgenic production using CRISPR/Cas gene-editing constructs via either injection or electroporation of fertilized eggs. This technology is replacing the generation of conventional knockout mice using embryonic stem cells and has made the technology more user friendly to a variety of investigators and allows NHGRI to be at the cutting edge of this new and important genomic editing technology in mammalian models. The core generated targeted transgenics using the CRISPR/Cas system for over 150 constructs since January 2014. Additionally, there were over 100 transgenic lines cryopreserved due to the efficiency of CRISPR/Cas to generate multiple alleles.